FoxO Forkhead transcription factors are major targets of insulin action and may play an important role in the pathogenesis of diabetes mellitus, a major cause of morbidity and mortality in the Veteran population. FoxO proteins play an important role in promoting hepatic glucose production, and the ability of insulin to suppress FoxO activity is thought to be important in maintaining glucose homeostasis. Based on studies in transgenic mice, we reported that FoxO proteins also contribute to the regulation of other metabolic functions in the liver, including lipd metabolism, and recent studies in knock in and knock out models support this concept. We previously found that transgenic expression of constitutively active FoxO1 suppressed the expression of SREBP-1c (a master regulator of lipogenic gene expression) and de novo lipogenesis (measured with 3H- tagged H2O) after eating, yet the mechanisms mediating this effect remain unclear. Based on recent findings, we have identified a novel mechanism that promises to shed new light onto the pathway mediating FoxO effects on lipid metabolism. Additional studies are planned to investigate specific mechanisms mediating effects of FoxO proteins on gene expression and metabolism in the liver.